Energy Compression and Stabilization of Laser-Plasma Accelerators.

Laser-plasma accelerators outperform current radio frequency technology in acceleration strength by orders of magnitude. Yet, enabling them to deliver competitive beam quality for demanding applications, particularly in terms of energy spread and stability, remains a major challenge. In this Letter, we propose to combine bunch decompression and active plasma dechirping for drastically improving the energy profile and stability of beams from laser-plasma accelerators. Realistic start-to-end simulations demonstrate the potential of these postacceleration phase-space manipulations for simultaneously reducing an initial energy spread and energy jitter of ∼1-2% to ≲0.1%, closing the beam-quality gap to conventional acceleration schemes.

Chirp Mitigation of Plasma-Accelerated Beams by a Modulated Plasma Density.

Plasma-based accelerators offer the possibility to drive future compact light sources and high-energy physics applications. Achieving good beam quality, especially a small beam energy spread, is still one of the major challenges. Here, we propose to use a periodically modulated plasma density to shape the longitudinal fields acting on an electron bunch in the linear wakefield regime. With simulations, we demonstrate an on-average flat accelerating field that maintains a small beam energy spread.

Effects of synthetic peptido-leukotrienes on bone resorption in vitro.

Peptido-leukotrienes are short-lived organic molecules known to have potent biological effects as mediators of inflammation, hypersensitivity and respiratory disorders. However, little is known concerning their effects on bone cells. We have shown previously that stromal cells isolated from a human giant cell tumor secrete 5-HETE (5-hydroxyeicosatetraenoic acid) and the peptido-leukotrienes, also known as the cysteinyl leukotrienes LTC4, LTD4, and LTE4. These eicosanoids were shown to stimulate the multinucleated giant cells obtained from these tumors to form resorption lacunae on sperm whale dentine. Here, we show that the peptido-leukotrienes also stimulate isolated avian osteoclast-like cells to form resorption lacunae and to increase their content of tartrate-resistant acid phosphatase. LTD4 increased 45Ca release from murine calvarial bone organ cultures, but not from fetal rat long bone cultures. Isolated avian osteoclast-like cells were chosen to perform receptor binding studies, as this population is the most homogeneous source of osteoclasts available. After the precursors had fused to form multinucleated cells, receptor binding assays were performed. Scatchard analysis of saturation binding data showed a single class of binding sites, with a dissociation constant (Kd) of 0.53 nM and a receptor density of 5,200 receptors per cell. Competition binding studies showed receptor specificity using a specific LTD4 receptor antagonist ZM 198,615. These data show that the peptido-leukotrienes activate highly enriched populations of isolated avian osteoclast-like cells, and also that specific LTD4 receptors are present in this cell population.

Healing and remodeling of articular incongruities in a rabbit fracture model.

Healing of 0.5 or 1.0-millimeter step-off defects associated with displaced intra-articular fractures of the medial femoral condyle was examined in fifty-four adult New Zealand White rabbits. The rabbits were treated with either immobilization for three weeks, intermittent active motion, or continuous passive motion for seven days. At twelve weeks, the healing and remodeling of the step-off defects were examined with use of contact-pressure maps on pressure-sensitive film, light microscopy (with hematoxylin and eosin or safranin-O staining), and scanning electron microscopy. Macroscopically, the sharp profile that had been present initially with both sizes of step-off defect had rounded off; however, there was less residual incongruity with the 0.5-millimeter step-offs than with the 1.0-millimeter step-offs. Among step-off defects of the same size, the method of treatment had no discernible effect on the macroscopic appearance of the surface of the joint. With fresh step-offs (the control group), the contact pressure of the cartilage on the elevated side was approximately three times greater than that at a distance from the step-off. On the depressed side, an unloaded zone extended approximately three times the height of the step-off, with an average width of 3.4 millimeters for the 1.0-millimeter step-offs and 1.6 millimeters for the 0.5-millimeter step-offs. After healing and remodeling, the unloaded zone still averaged 2.5 millimeters in width for the 1.0-millimeter step-offs but had decreased to only 0.35 millimeter in width for the 0.5-millimeter step-offs. For seven of the nine 0.5-millimeter step-offs, the contact pressure in the previously unloaded zone ranged from 0.5 to 1.5 megapascals, with a mean of 0.8 megapascal (40 per cent of the normal mean contact pressure at this location). Under light microscopy, the cartilage on the elevated side of the healed step-offs had decreased in thickness, was displaced toward the defect and tapered toward the depressed side, and ended in a hypocellular tissue flap. In contrast, the cartilage on the depressed side had thickened as a result of hyperplasia of the chondrocytes and hypertrophy of the cartilage and had failed to establish continuity between the sides of the defect. There was a marked increase in the subchondral vascular bed and re-establishment of the subchondral plate. With the exception of the aforementioned hypocellular tissue flap, safranin O stained the cartilage on both levels of the step-off uniformly, which indicated the absence of glycosaminoglycan depletion.(ABSTRACT TRUNCATED AT 400 WORDS)

Magnesium deficiency-induced osteoporosis in the rat: uncoupling of bone formation and bone resorption.

Magnesium (Mg) intake has been linked to bone mass and/or rate of bone loss in humans. Experimental Mg deficiency in animal models has resulted in impaired bone growth, osteopenia, and increased skeletal fragility. In order to assess changes in bone and mineral homeostasis that may be responsible, we induced dietary Mg deficiency in adult Simonsen albino rats for 16 weeks. Rats were fed either a low Mg diet (0.002 percent) or a normal control Mg diet (0.063 percent). Blood was obtained at baseline, 4 weeks, 8 weeks, 12 weeks and 16 weeks in both groups for serum Mg, calcium, PTH, and 1.25(OH)2-vitamin D determinations. Femora were harvested at 4 weeks and 16 weeks for mineral analysis and histomorphometry. Serum Mg fell in the Mg depleted group to 0.6 mg/dl (mean) by 16 weeks (controls = 2.0 mg/dl). The serum calcium (Ca) concentration was higher in the Mg depleted animals at 16 weeks, 10.8 mg/dl (controls = 8.9 mg/dl). Serum PTH concentration fell progressively in the Mg deficient rats to 30 pg/ml by week 16 (control = 96 pg/ml). Serum concentration of 1.25(OH)2-vitamin D also fell progressively in the Mg deficient animals by 16 weeks to 14 pg/ml (control = 30 pg/ml). While the percent ash weights of Ca and phosphorus in the femur were not different at any time point, the percent ash weight of Mg progressively fell to 0.54 percent vs control (0.74 percent) by 16 weeks. The percent ash weight of potassium also fell progressively in the Mg deficient group to approximately 30 percent of control by 16 weeks. Histomorphometric analyses showed a significant drop in trabecular bone volume in Mg deficient animals by 16 weeks (percent BV/TV = 13.2 percent vs 17.3 percent in controls). Evaluation of the endosteal bone surface features showed significantly greater bone resorption in the Mg depleted group as reflected in increased number of tartrate-resistant positive osteoclasts/mm bone surface (7.8 vs 4.0 in controls) and an elevated percent of bone surface occupied by osteoclasts (percent OcS/BS = 12.2 percent vs 6.7 percent in controls. This increased resorption occurred in the presence of an inappropriate lowered bone forming surface relative to controls; a decreased number of osteoblasts per mm bone surface (0.23 vs 0.94 in control) and a decrease in percent trabecular surface lined by osteoid (percent OS/BS = 0.41 vs 2.27 percent in controls) were also noted. Our findings demonstrate a Mg-deficiency induced uncoupling of bone formation and bone resorption resulting in a loss of bone mass. While the fall in PTH and/or 1.25(OH)2-D may explain a decrease in osteoblast activity, the mechanism for increased osteoclast activity is unclear. These data suggest that Mg deficiency may be a risk factor for osteoporosis.

Neutrophilic phagocytosis in autoimmune thrombocytopenia purpura.

In vivo neutrophil phagocytosis was demonstrated by transmission electron microscopy (TEM) in the peripheral blood of two half-sibs with hereditary thrombocytopenia. These sibs have had a lifetime documented history of thrombocytopenia. Light microscopy morphology and histochemistry studies of blood and marrow were normal, similar studies of blood from available members of the kinship were also normal. Scanning electron microscopy (SEM) of platelets from each member of the kinship showed normal dendritic and spreading formation. In the TEM thin sections of platelet buffy coats, neutrophil ingestion of platelets was common and all stages of the phagocytic process were noted--from platelet-neutrophil intimacy to the formation of myelin bodies in phagosomes. The clinical courses over a 10-year period were mild, requiring rare therapeutic interventions. The chronic thrombocytopenia, lengthy mild course, modestly elevated platelet-associated immune globulin, normal aggregation and survival studies, and autoimmune neutrophil reaction to platelets allowed classification of these patients as hereditary thrombocytopenia purpuras.

Improvements in dehydration and cement line staining for methacrylate embedded human bone biopsies.

Undemineralized methacrylate embedded bone biopsies and other bone specimens can be processed much more rapidly by application of acidified 2,2-dimethoxypropane (DMP) dehydration, which requires two hours, than by traditional graded ethanol dehydration, which requires at least four days. This shortened processing time is valuable when biopsy results are urgently needed to detect osteomalacia or to determine bone features prior to possible parathyroidectomy. We have processed over 200 bone specimens with DMP and have compared DMP dehydration to graded ethanol dehydration in 11 biopsies in which two plugs were available from the same patient. DMP dehydration does not compromise the following: tetracycline retention, Goldner's stain, acid phosphatase localization or histochemical identification of aluminum. Cement lines, which provide a record of past remodelling, are useful in clinical interpretation of bone biopsies. We have adapted two stains, toluidine blue and methylene blue/basic fuchsin, for improved cement line identification. Five-micrometer sections individually demineralized in acetate buffer prior to cement line staining show best results with toluidine blue at pH 5.5 and with methylene blue/basic fuchsin at pH 2.5-3.5.

Synovisol as an irrigant for electrosurgery of joints.

The appropriate irrigation fluid for use during arthroscopic procedures should be selected on the basis of fluid-tissue and fluid-instrumentation compatibility. This study describes a new irrigation fluid, Synovisol, that is isomolar, nonhemolytic, nonantigenic, has a low viscosity, and is nonconductive. The rabbit knee was used as a model to demonstrate the immediate and long-term (3 weeks) effects of irrigation with Synovisol compared with water, normal saline, mannitol, sorbitol, glycine, and with nonirrigated controls. Results were assessed by light- and electron-microscopic evaluation of synovium and cartilage dissected from rabbit knees. While the greatest amount of damage was seen in water-treated samples, significant effects were noted with other irrigants compared with Synovisol and controls. Long-term animals showed recovery of tissues in all cases. Systemic effects evaluated by measuring plasma glycerol levels showed a transient increase that peaked at 20 min. No hemolysis was detected and kidney morphology was normal. The physiological, electrocompatible, simplicity of formula, low cost, and long-shelf-life properties of this solution makes it a fluid uniquely suited to arthroscopy.

Methotrexate eluted from bone cement: effect on giant cell tumor of bone in vitro.

The effectiveness of methotrexate eluted from polymethylmethacrylate on cell lines established from giant cell tumor of bone was investigated in vitro to determine the possible efficacy of this treatment. Elation of methotrexate from polymethylmethacrylate beads and boluses was shown in vitro to be dose dependent and limited by the size of the bolus. Cytocidal activity of methotrexate elated from polymethylmethacrylate beads prepared without monomer and of boluses of polymethylmethacrylate with the same dose of methotrexate prepared with monomer against 2 human giant cell tumor cell lines was statistically significant at 24 hours in culture. Statistical significance occurred at 24 hours in culture. Activity was maintained in vitro after 17 days. These experiments showed that eluted methotrexate remained effective against tumor cells after exposure to thermal changes during polymerization of polymethylmethacrylate. While extensive curettage of giant cell tumor of bone followed by filling in the defect with polymethylmethacrylate has become a common treatment, a local adjuvant is necessary to reduce further risk of local recurrence. A potential alternative to cryosurgery or instillation of phenol is the use of methotrexate impregnated polymethylmethacrylate to treat residual microscopic disease after curettage. This method may provide locally effective chemotherapy without the risks of systemic toxicities.

Alkaline and acid phosphatase demonstration in human bone and cartilage: effects of fixation interval and methacrylate embedments.

Human bone and cartilage specimens were evaluated for acid and alkaline phosphatase localization following varying fixation periods for fresh or frozen tissue. Formalin fixations of up to 183 hr were followed by embedment in methyl methacrylate; frozen tissue was examined either without fixation or following fixation for up to 1 hr and subsequent glycol or methyl methacrylate embedding. The humeral epiphysis of a young patient with osteogenic sarcoma showed optimum acid and alkaline phosphatase localization following fixation for periods up to 15 hr and embedding in methyl methacrylate. Frozen costochondral junction from a newborn with osteogenesis imperfecta type II showed optimum acid and alkaline phosphatase localization following 30 min fixation in formalin and embedding in methyl methacrylate or after 5 min fixation and embedding in glycol methacrylate.

Bone response to invading tumors with spindle cell components: a report of findings in two patients.

Two case studies are presented in which quantitative bone histomorphometry is used to analyze bone changes in adult patients with diagnosed spindle cell sarcoma. Three tumor-involved sites and one noninvolved site from the iliac crest of patient 1 were evaluated. In the involved sites the percentage trabecular bone volume (11.0%) and the number of osteoblasts (0.6 cell/mm2) were significantly reduced, osteoid volume was significantly increased (8.1%), and woven osteoid was present. The total eroded surface (6.8%) was also significantly increased. In the noninvolved site the number of osteoblasts was decreased and both the percentage eroded and percentage osteoclast surfaces were increased. In the femoral epicondyle specimen from patient 2 the number of osteoblasts was 27.0 cells/mm2, percentage osteoid volume was 18.4%, percentage osteoid surface was 62.9%, and osteoid thickness was 20.0 microns. In tumor-involved sites in both patients indices of active bone resorption were similar and normal. These two case studies indicate that (1) distinctive morphologic changes occur in bone invaded by spindle cell sarcoma, and that (2) changes affect bone formation to a greater extent than bone resorption. Bone alterations are probably local in nature and related to the extent and duration of tumor invasion and the influence of local tumor factor(s).

Bone remodelling in the presence of chondrosarcoma: histomorphometry.

Accurate knowledge of tissue changes near bone tumors can contribute to a better understanding of tumor behavior. We have used tumor ultrastructure and quantitative bone histomorphometry to evaluate local bone/tumor features associated with a low grade chondrosarcoma in a 39-year-old male. Three noninvolved sites and two sites near the tumor in the proximal femur were studied with bone morphometry. Bone near the tumor showed increased percent osteoid surface, percent osteoid volume and fraction of osteoid surface lined by osteoblasts compared to distant noninvolved sites. Both the number of osteoblasts and mean individual osteoblast size were significantly increased compared to noninvolved sites. Osteoclast number and percent osteoclast surface were also increased near the tumor. Ultrastructural studies of tumor tissue revealed two types of tissue: synthetic mesenchymal cells and cartilage tissue. Results indicate increased bone formation and resorption near the tumor. These local bone changes may possibly reflect responses to local tumor factors and depend on the extent of the tumor.

Magnesium deficiency induces bone loss in the rat.

Disorders in which magnesium (Mg) depletion is common have an associated high incidence of osteoporosis. Mg depletion in humans results in hypocalcemia, low serum parathyroid hormone (PTH) and 1, 25(OH)2-vitamin D levels, as well as PTH and vitamin D resistance which may serve as mechanisms for the development of osteoporosis. In order to determine if isolated Mg depletion will result in bone loss, we have induced dietary Mg deficiency in the rat. Adult (290 g) female rats were given either a low-Mg diet (2 mg/100 g chow; n = 6) or a normal control Mg diet (63 mg/100 g chow; n = 6). Dietary calcium (Ca) was normal in both groups (592 mg/100 g chow). At 12 weeks, blood was obtained for serum Mg, Ca, PTH, 1,25(OH)2-vitamin D, and osteocalcin determinations. The rats were then euthanized and the femurs obtained for mineral analysis and histomorphometry. Serum Mg in the low-Mg group was less than control (0.4 +/- 0.2 vs. 1.9 +/- 0.2 mg/dl, p < 0.001; mean +/- SD) while serum Ca was higher (11. 7 +/- 0.5 vs. 9.3 +/- 0.4 mg/dl, p < 0.001). PTH was suppressed in the Mg-deficient group (36 +/- 16 vs. 109 +/- 30 pg/ml in controls, p < 0.002). Serum 1,25(OH)2-vitamin D was also suppressed in the Mg-deficient animals (7.1 +/- 4.8 vs. 28.5 +/- 8.2 pg/ml in controls, p < 0.002). Serum osteocalcin levels were not different (19.8 +/- 2.5 ng/ml in Mg-deficient rats vs. 15.3 +/- 3.4 ng/ml in controls). While the ash weight of Ca and phosphorus in the femur did not change, the ash weight of Mg fell (low-Mg group 0.55 +/- 0.01%, controls 0.65 +/- 0.02%, p < 0.001). Histomorphometry demonstrated reduction in bone mass; the trabecular bone volume in the femur of the low-Mg group was reduced from control (7.7 +/- 0.2 vs. 13.7 +/- 1.9%, p < 0.002). A surprising new observation was an increase in osteoclast (OC) bone resorption with Mg depletion. The number of OC per millimeter bone surface was 16.9 +/- 1.3 in the low-Mg group versus 7.8 +/- 1.5 in controls (p < 0.001). The percentage of bone surface occupied by OC was 38.3 +/- 3.7 in the low-Mg group versus 17.7 +/- 2.4 in controls (p < 0.001). This increased resorption occurred with an inappropriate non-altered bone-forming surface relative to control (% osteoid surface: low-Mg group 2.4 +/- 0.7 vs. controls 2.6 +/- 0.4; % osteoid volume: low-Mg group 0.25 +/- 0.09 vs. controls 0.38 +/- 0.06; number of osteoblasts per millimeter bone surface: low-Mg group 0.9 +/- 0.3 vs controls 1.3 +/- 0.3). No increase in bone-forming surface or osteoblast number despite an increase in OC-resorbing surface and OC number strongly suggests impaired activation of osteoblasts and an uncoupling of bone formation and bone resorption. Our data demonstrate that Mg depletion in the rat alters bone and mineral metabolism which results in bone loss.

Alteration in osteoblast cell number and cell activity in the presence of invading malignant fibrous histiocytoma.

Correct prediction of tumor behavior and interpretation of local factors in the tumor microenvironment rely in part upon accurate determination of tissue changes after tumor invasion. The authors examined local bone changes in primary malignant fibrous histiocytoma (MFH) of bone in a 59-year-old woman. Three noninvolved and three tumor-involved sites were evaluated by quantitative determinations of bone structural and dynamic features. Compared to noninvolved sites, tumor-involved bone was characterized by significantly increased osteoblast index (89.4 +/- 15.6 [mean +/- SEM] versus 7.3 +/- 6.0, P = 0.008), percent osteoid area (12.1 +/- 2.7 versus 1.2 +/- 0.5, P = 0.02), percent of trabecular surface covered by osteoid (70.0 +/- 6.0 versus 14.5 +/- 4.8, P = 0.002), and percent osteoid lined by osteoblasts (36.4 +/- 3.6 versus 3.7 +/- 3.0, P = 0.002). Bone 7.8 mm distant from invading tumor cells showed features characteristic of noninvolved sites, whereas bone completely surrounded by tumor showed markedly decreased osteoblast features. Osteoblast function also was affected by tumor; the amount of matrix laid down per day bore a significant positive correlation with the osteoblast index. These data indicate the following: distinctive bone morphologic changes occur in situ during invasion by MFH; changes affect aspects of bone formation but not resorption during invasion; both osteoblast number and osteoblast activity are significantly altered; and changes are local in nature and probably reflect the osteoblast response to local tumor factor(s) and are dependent upon the extent of tumor invasion.

Effects of microgravity on bone healing in a rat fibular osteotomy model.

Bone healing was investigated histologically in a rat fibular osteotomy model subjected to microgravity (shuttle flight STS-29) and the tail suspension microgravity simulation model. Exposure to microgravity or tail suspension occurred during the last 5 days of a 10-day healing period. Periosteal osteogenesis and the development of vascular channels in both experimental groups were similar to that observed in a weightbearing control group. Chondrogenesis was more advanced in weightbearing rats than in either flight or tail-suspended rats. Angiogenesis in the osteotomy gap was more advanced in weightbearing and tail-suspended rats than in the flight group. These findings suggest that bone healing may be impaired during space travel. Interpretation of the findings is complicated by observations that flight and suspended rats lost weight during the flight period and that suspended rats consumed less water than control rats. Tail suspension did not produce the same pattern of healing as spaceflight; therefore, long-term studies of bone healing, conducted entirely in the microgravity environment, are needed to distinguish metabolic from mechanical influences and to determine whether effective fracture consolidation will occur in the absence of gravitational forces.

Characterization of a cell line derived from a human giant cell tumor that stimulates osteoclastic bone resorption.

Giant cell tumors of bone are common but unusual tumors that are comprised of multiple cell types. Most attention has been focused on the giant cells, which resemble osteoclasts morphologically and functionally. This study examines the properties of a cell line derived from mononuclear cells from one of these tumors, since it appears likely that these cells may be able to influence the activities of cells with the osteoclast phenotype. This cell line, C433, has the following characteristics: (1) it represents undifferentiated cells, not recognized by any known antigenic markers for leukocytes; (2) it contains tartrate-resistant acid phosphatase; (3) it responds to the osteotropic factors 1,25 dihydroxyvitamin D3, insulin-like growth factor I and II, but not to parathyroid hormone; (4) it forms sarcomas in nude mice; and (5) it produces an activity that stimulates isolated avian and rat osteoclasts to resorb bone. This cell line may be useful in examining interactions between osteoclasts and accessory cells involved in bone resorption.